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Chapter 63 - Polyphenols against Skin Aging

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Abstract

The skin is the largest organ of the body with a surface area of approximately 1.5–2.0 m2. It protects the internal organs of the body by acting as an effective barrier against the detrimental effects of environmental and xenobiotic agents (e.g., extrinsic harmful chemicals and genotoxics). Strong or chronic exposition to a variety of external stresses (e.g., ultraviolet radiation aka solar UV) may contribute to premature skin aging, immune-suppression, and tumorigenesis/carcinogenesis (i.e. tumor/cancer formation). Therefore, a search for prevention strategies to circumvent such unfavorable outcomes is being constantly pursued. Polyphenols (aka polyhydroxyphenols) represent a superfamily of diverse naturally occurring phytochemicals. An increasing number of studies on vertebrates and invertebrates have shown that these compounds modulate many signaling pathways, and subsequently exert numerous biological activities (e.g., significant antioxidant, chemopreventive, immune-modulatory, cell repair and photo-protective effects) as well as potential health benefits (e.g., prevention of aging, reduction in cancer incidences and other inflammatory-state diseases). Among the several hundreds of dietary polyphenols (plant nutraceuticals aka phytonutrients), some constitute a promising approach to remedying many skin conditions (i.e., prevention and treatment of skin aging and diseases). The protective skin aging effects exhibited by polyphenols may, however, partially depend on their molecule characteristics, the food matrix, and/or on their bioavailability, which does not always depend on the overall intake/consumption. Eventually, natural purified polyphenols or polyphenol-rich plant extracts (semi-synthetic or synthetic) might supplement skin chemotherapeutics, our sun protection armamentarium, and further enhance the benefit of esthetic techniques (e.g., microdermabrasion). Thereby, polyphenols are also gaining popularity as ingredients in cosmetic formulations (cosmeceuticals). In this chapter, we outline the current progress in skin aging intervention studies using polyphenols (e.g., purified polyphenols, dietary, or topical rich-polyphenols products).
CHAPTER
63c0063
Polyphenols against Skin Aging
Farid Menaa*, Abder Menaa
and Jacques Tre
´ton
*Fluorotronics, Inc., Department of Oncology, Regenerative Medicine and Nanomedicine, San Diego, CA, USA
Centre Me
´dical des Guittie
`res, Department of Nutrition, Dermato-Esthetics and Anti-Aging Medicine, Saint-Philbert
de Grand Lieu, France
Universite
´Paris V-Rene
´Descartes, Department of Geriatry and Gerontology, Centre de
Recherches des Cordeliers, Paris, France
s0010 1. INTRODUCTION
p0010 Aging is associated with a gradual decline of physi-
ological and cognitive functions.
1
Over the past two
decades, significant progress has been made in eluci-
dating the molecular mechanisms of aging,
2,3
an active
but still challenging area. Hundreds of genetic factors,
called longevity-related genes, have been identified to
modulate lifespan and healthspan in model organisms
ranging from yeast (e.g., Sacharromyces cerevisiae),
worms (e.g., Caenorhabditis elegans), flies (e.g.,
Drosophila melanogaster), and rodents (e.g., Mus muscu-
lus,Rattus norvegicus). Among them, a large number of
the longevity-related genes fall into three conserved
nutrient sensing pathways: target-of-rapamycin (TOR),
insulin/IGF-1-like signaling (IIS), and sirtuin path-
ways.
4,5
The recent studies have shed light on some of
the mechanisms involved in aging processes, and pro-
vide valuable guidance for developing and promoting
effective healthy skin aging interventions.
6
p0015 Skin aging is a complex, progressive and
inevitable biological process. Although it is primarily a
physiological process (i.e., the so-called chronologic
aging) involving our own genetic background, it may
also become a pathological process (i.e., the so-called
premature aging). Premature skin aging is manifested by
accelerated induction of wrinkling, scaling, roughness,
dryness, laxity, as well as mottled pigment abnormali-
ties including hypo-pigmentation and hyper-
pigmentation, and can be caused by the detrimental
effects of xenobiotics agents or environmental (e.g.,
chronic exposure to solar ultraviolet radiation-induced
oxidative stress aka hotoaging, pollution, cigarette
smoke, extreme temperature change).
7,8
p0020One of the major features of aging skin is the pro-
gressive proteolytic degradation of cutaneous elastic
fibers that cannot be adequately replaced or repaired by
adult dermal fibroblasts.
9
In fact, the impact of both
chronological aging and hotoaging on the skin appears
particularly concerning when enhanced oxidative stress
is involved. Interestingly, a recent study showed quan-
titative and qualitative differences in the oxidative
stress generated either by chronological aging or by
hotoaging in the skin of hairless mice.
10
Indeed, while
the lipid peroxides level was increased in both skin
types, and so would represent a good parameter to
determine the oxidative stress, a difference in the
decay capacity of lipid membrane turnover was noticed
between chronological and hotoaging skin.
10
Importantly, neither superoxide dismutase (SOD),
which remained unchanged, nor catalase, which
increased with chronologic aging and decreased in irra-
diated mice, could have been considered as good bio-
markers of oxidative stress.
10
p0025Plants are the source of important products with
nutritional and therapeutic value. There is emerging
evidence that topical application or oral intake of some
polyphenol-rich plant extracts can reduce a number of
degenerative diseases and skin conditions such as skin
aging.
11,12
Polyphenols represent a superfamily of
diverse naturally occurring plant chemicals, and are
abundant micronutrients in our diet (e.g., vegetables,
fruits, flowers, nuts, seeds).
13,14
The protective health
effects exerted by polyphenols as neutraceuticals
depend not only on the dietary intake but also on their
systemic bioavailability.
13,14
Indeed, the most abundant
polyphenols in our diet are not necessarily those that
have the best bioavailability profile.
13
The
819
Polyphenols in Human Health and Disease.
DOI: http://dx.doi.org/10.1016/B978-0-12-398456-2.00063-3 ©2014 Elsevier Inc. All rights reserved.
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bioavailability and sources of polyphenols and
polyphenol-containing foods has been previously
reviewed,
13,14
showing that it mainly depends on: (1)
their intestinal absorption during which the microflora
of each given individual plays an important role in the
catabolism of polyphenols and the production of some
active metabolites, (2) their chemical structure (e.g.,
glycosylation, esterification, and polymerization), (3)
their inclusion in the food matrix, and (4) their excre-
tion back into the intestinal lumen.
p0030 Globally, there are three main types of polyphenols:
the flavonoids, the stilbenes, and the lignans, which are
classified by the number of phenol rings they contain as
well as the binding properties of the ring
structures.
1114
The phenol rings are comprised of phe-
nyl and hydroxyl group structures that possess diverse
biological activities such as anti-inflammatory,
immune-modulatory and antioxidant properties.
11,12,15
Further, each class of these phytochemicals can be sub-
classified in accordance to the interactions of their
respective phenyl rings to carbon, oxygen, and organic
acid molecules.
13,14
Thereby, flavonoids represent a large
class of edible polyphenols, and are divided into six
main sub-classes: (1) flavonols (highly concentrated in
onions, apples, red wine, tea, broccoli and Ginkgo bilo-
ba), (2) flavones (a good amount in the herb chamomile),
(3) isoflavones (predominant in soy), (4) flavanones
(largely present in citrus fruits), (5) anthocyanidins
(abundant in berries and cherries), and (6) flavanols (i.e.,
catechins, mainly found in red wine, tea and apples),
among which the most abundant is (2)epigallocate-
chin-3-gallate (EGCG), extensively studied because of
its potent therapeutic effects in skin.
16,17
Stilbenes (aka
stilbenic phytoalexins) are found in low quantities in
the human diet, and are mainly represented by resvera-
trol that exist in both cis and trans isomeric forms,
mostly glycosylated. Resveratrol has been detected in
more than 70 plant species (e.g., red grapes, particularly
in the fresh skin, berries, peanuts, red wine, grape
juice), and presents potential benefit against premature
skin aging.
13,14,18,19
Most lignans are naturally present in
the free form, while their glycoside derivatives repre-
sent a minor form. They are also found in low quanti-
ties in the human diet (e.g., mainly present in linseed,
nuts, and whole grain cereals).
13,14
p0035 Being widely abundant and relatively inexpensive,
the use of polyphenols is highly attractive to researchers
as a cost-effective alternative or as a strategy to supple-
ment current skin pharmacologic therapeutics,
20
skin
protection agents (e.g., sunscreens)
2124
and cosmetic-
esthetic techniques (e.g., microdermabrasion).
25
p0040 Since the structure, metabolism, pharmacokinetics,
pharmacodynamics, sources and amounts of relevant
polyphenols have been extensively reviewed,
13,14
our
manuscript aims to provide an update about the
studies of polyphenols (e.g., purified polyphenols,
polyphenol-rich plant extracts) that claim potential
benefits (i.e., biologic and clinical effects) against skin
aging, being aware that further clinical studies are still
required to uneqivocally prove their efficacy and
safety.
26,27
s00152. POLYPHENOLS BENEFITS ON SKIN
AGING: AN OVERVIEW
p0045Skin, the largest organ of the body, is the organ in
which changes associated with aging are most visible.
The skin is made up of three main layers: the hypoder-
mis, the dermis, and the epidermis.
28
The hypodermis
is the deepest section of skin, and is primarily a place
of connection and fat storage.
28
The epidermis is made
up mostly of keratinocytes, is rich in reactive oxygen
species (ROS), detoxifying enzymes and in low molec-
ular weight antioxidant molecules, and also contains
melanocytes, Merkel cells, and Langerhans cells.
28
The
primary function of the epidermis is to provide a
weather- and water-proof layer to protect the body.
28
The dermis contains most of the connective tissues of
the skin, as well as nerve endings, sweat glands, and
hair follicles.
28
p0050Similar to the entire organism, skin is subject to an
unpreventable intrinsic aging process (e.g., respiration-
induced oxidative stress). Intrinsic skin aging is char-
acterized by atrophy of the skin with loss of elasticity
and slowed metabolic activity.
29,30
Additionally, skin
aging is influenced by exogenous/extrinsic factors
(e.g., sunlight/UV radiation (UVR) and other atmo-
spheric conditions) that can lead to premature skin
aging,
3133
resulting in hypertrophic repair response
with thickened epidermis and increased melanogene-
sis, as well as even more striking changes in the der-
mis (i.e., massive elastosis, collagen degeneration,
twisted and dilated microvasculature).
29,30
p0055In normal/unstressed cells, there is a constant pro-
duction of ROS from the mitochondria, which is
balanced by the production of antioxidant enzymes in
the cell, such as SOD, catalase, and glutathione (GSH)
peroxidase.
34
When a cell comes under stress, this
balance is interrupted, and the ROS can overwhelm
the cells and lead to a change in normal cellular beha-
viors.
35,36
Therefore, despite their morphological and
pathophysiological differences, intrinsic and extrinsic
aging (i.e., chronologic skin aging and skin hotoaging,
respectively) share several molecular similarities. In
summary, the central aspects of the skin aging are
reflected by the intracellular and extracellular oxida-
tive stress initiated by two main events: (1) the forma-
tion of ROS, and (2) the induction of matrix
metalloproteinases (MMPs).
820 63. POLYPHENOLS AGAINST SKIN AGING
6. DIVERSE DISEASE AND PHYSIOLOGICAL STATES MODIFIED BY POLYPHENOLS
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p0060 ROS (e.g., singlet oxygen, superoxide, peroxyl radi-
cals, hydroxyl radicals, and peroxynitrite),
37
overba-
lances the antioxidant defense system potential of the
skin structure (i.e., horny layer, epidermis and der-
mis).
38,39
ROS react with nucleic acids, proteins, glucids
and fatty acids, causing oxidative damage (i.e., lipid
peroxidation),
40
and contribute to chronologic skin
aging,
37,40,41
pathogenesis of inflammatory processes
and allergic responses in the skin,
29
as well as to skin
hotoaging and skin cancer development (e.g., photo-
carcinogenesis).
40
The roles and mechanisms of ROS
metabolism (i.e., generation and elimination) in the
body, as well as the effects of ROS generated in the skin
(e.g., free radical damage, cell-mediated responses asso-
ciated with the mitogen-activated protein kinase
(MAPK) activity), have been previously reviewed.
37,38
p0065 The induction of MMPs, which leads to the accumu-
lation of fragmented collagen fibrils, which prevents
neocollagenesis and accounts for the further degrada-
tion of the extracellular matrix (ECM) by means of posi-
tive feedback regulation.
41
For instance, it is known that
after UVR-induced ROS, MMP-1 (aka collagenase-I),
-3, -9 levels are increased, causing collagen and elastin
degradation before forming coarse wrinkles and sag-
ging skin.
42
p0070 In recent years, epidemiological and biochemical
studies have shown that the occurrence of various dis-
eases (e.g., cancer, degenerative and cardiovascular
pathologies, premature skin aging) has been reduced,
notably because of the antioxidative effects of polyphe-
nols. Indeed, antioxidants such as flavonoids and phe-
nolic acids play a main role in fighting ROS, and the
inhibiting mechanisms of photoaging by polyphenols
(e.g., inhibition of MMP-1, elastase and hyaluronidase)
are being unraveled in order to develop agents able to
slow down the aging process.
42,43
p0075 In this regard, the evaluation of local polyphenol-
based anti-aging therapy (e.g., polyphenol-rich sunsc-
reens and skin care products),
21,2325,39,40,42
as well as the
potential benefit of dietary polyphenol,
1619,22,43
remains
an active but challenging field of research. Briefly, it is
now well-accepted that topical polyphenol-rich products
(i.e., cosmeceutics) can partially “reverse” the clinical
and histologic changes in the epidermis and dermis
induced by the combination of sunlight exposure and
chronologic aging (e.g., repair of keratinocyte ultrastruc-
tural damage, distribution of melanin, deposition of new
papillary dermal collagen, improvements in vasculature,
normalization of hyperkeratinization, increased epider-
mal thickness and dermal glycosaminoglycan (GAG)
such as hyaluronic acid).
23
Thus, the topical use of such
agents may favorably supplement sunscreens providing
additional anti-aging (and anticarcinogenic) skin bene-
fits.
24,44
Besides, the protective effects on skin aging
exerted by polyphenol-rich food products (i.e.,
neutraceuticals) depend not only on the dietary intake,
the source plant, the polyphenolic content and nature in
the food matrix, but also on the polyphenols systemic
bioavailability.
13,14
Some herbs such as green tea (EGCG-
rich plant),
16,17
or some fruits such as grapes (resvera-
trol-rich plant),
18,19
have been shown as promising edible
products against skin aging. Further, polyphenol-rich
agents should strengthen the use of some esthetic techni-
ques, supporting the role of topical antioxidants as anti-
aging factors. For instance, a recent study using adult
female volunteers (n510), reported that the addition of
skin polyphenolic antioxidant-based serum enhanced
the dermatologic changes (i.e., increased epidermal and
papillary dermal thickness, enhanced fibroblast density,
increased hyalinization of the papillary dermis with
newly deposited collagen fibers). This was seen follow-
ing facial treatments using microdermabrasion, a reli-
able, non-invasive tool for facial rejuvenation.
25
p0080Nevertheless, one should also keep in mind that some
polyphenols could be a double-edged sword for the
human skin, exerting both protective (i.e., as antioxi-
dants) and damaging actions (i.e., allergic reactions,
contact dermatitis, phytodermatoses, photo-phytoder-
matoses, and enhanced UV-induced apoptosis).
36,37,45
p0085Anyhow, we believe that skin, as the largest
exposed organ, needs aggressive research as well as
new, multidisciplinary approaches for its management.
s00203. POLYPHENOLS WITH POTENTIAL
BENEFITS IN ANTI-AGING PROCESS
p0090Although there is a paucity of clinical studies con-
cerning the efficacy of polyphenols as topical
anti-aging agents, most relevant studies highlighting
the biological effects of active polyphenols (e.g., resver-
atrol, EGCG, genistein) for their possible development
and use as anti-aging cosmeceutics (i.e., polyphenol-
rich topical agents), adjuvant therapeutics or even neu-
traceutics are reviewed in this chapter. As previously
evoked, some pharmacologically active polyphenols
are capable of preventing the occurrence of skin aging
(chronologic and/or photo-induced or photo-
independent premature skin aging as seen in some
inherited disorders such as Costello or Werner syn-
dromes) and skin diseases (e.g., skin cancers), as well
as reducing the severity of UV-induced skin
damage.
21,2325,39,40,42,46,47
s00253.1 Resveratrol
p0095Resveratrol (3,5,40-trihydroxy-trans-stilbene), is a
phytoalexin antioxidant derived from natural products
such as the skin of red grapes, peanuts, blueberries
8213. POLYPHENOLS WITH POTENTIAL BENEFITS IN ANTI-AGING PROCESS
6. DIVERSE DISEASE AND PHYSIOLOGICAL STATES MODIFIED BY POLYPHENOLS
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and cranberries.
13,14
Resveratrol has received extensive
attention through the link with the “French paradox,”
and later with its chemopreventive activity demon-
strated in vitro and in animal cancer models.
18,4851
A
plethora of laboratory investigations has provided evi-
dence for the multi-faceted properties of resveratrol,
and suggests that resveratrol may target aging by reg-
ulating inflammation and oxidative stress.
18
Thereby,
resveratrol displayed a protective action on skin aging
and various disorders associated with aging.
18,19,5254
p0100 A recent study found that resveratrol, used as a
radioligand (i.e.,
3
H resveratrol), exert anti-apoptotic
effects by acting on specific plasma membrane poly-
phenol binding sites in the human skin (especially in
the epidermis) exposed to nitric oxide (NO) free radi-
cal donor sodium nitroprusside (SNP).
55
In another ex
vivo study, resveratrol treatment blocked
UVB-mediated activation of the nuclear factor-kappa B
(NF-κB) pathway in the normal human epidermal ker-
atinocytes (NHEK), in a dose- and time-dependent
fashion.
52
Further, it was shown that resveratrol pro-
tects human keratinocytes (HaCaT) from UVA-
induced oxidative stress damage by downregulating
Kelch-like ECH-associated protein 1 (Keap1) expres-
sion.
56
However, there are still a few roadblocks in the
way of this promising agent regarding its translation
from the bench to the bedside. For instance, an inde-
pendent and contradictory study showed that resvera-
trol sensitizes human keratinocytes to UVA-induced
apoptosis by a mechanism that involves a decrease of
the mitochondrial membrane potential, resulting in
opening of the mitochondrial permeability transition
pores.
46
Further, data reporting the effects of resvera-
trol consumption in a capsule versus food form are
conflicting, providing uncertainties on long-term
dosing.
18
p0105 Besides, based on a few in vivo studies, it appears
that the prospects are very bright for the possible use of
resveratrol in skin aging and diseases. For instance,
studies
53,5759
have shown that a topical application of
resveratrol to SKH-1 hairless mice skin results in signif-
icant inhibitions of UVB-mediated effects such as
decreases in: (1) skin edema and hyperplasia, (2)
inflammation, (3) infiltration of leukocytes into the epi-
dermis and dermis, (4) cyclooxygenase-2 (COX-2) level,
(5) ornithine decarboxylase (ODC), (6) hydrogen perox-
ide (H
2
O
2
), (7) lipid peroxidation, (8) proliferating-cell
nuclear antigen (PCNA) protein level in the epidermis,
(9) cellular proliferations (Ki-67 immuno-staining), (10)
established markers of tumor promotion, (11) surviving
activity and expression levels, and (12) MAPK-1/2 and
MAPK kinase (MEK-1). Conversely, increases in p53
and p53-downstream WAF1/p21 protein levels were
noticed, significantly reversing the UVB-mediated
responses in these proteins.
58
p0110Topical application of resveratrol to the skin
appears to be a better option in mammals than oral or
systemic administration because of its rapid metabo-
lism into glucuronides and sulfonates by the intestine
and liver (i.e., within 3060 minutes after administra-
tion), which leads to a poor plasmatic bioavailability.
59
Possible scenarios for improving the bioavailability
and efficacy of resveratrol have been suggested,
60,61
and include: (1) combination of resveratrol with agents
that can inhibit the in vivo metabolism of resveratrol,
(2) use of nano-formulations (nanoparticle-, hydrogel-,
nanosuspension-mediated delivery systems), (3) syn-
thesis and/or evaluation of analogs of resveratrol with
improved bioavailability, (4) careful evaluation of con-
jugated metabolites of resveratrol, which may be
deconjugated at the target organ to elicit a biological
response.
p0115Nowadays, a number of resveratrol-supplemented
skin care products and cosmetics are available in the
market. However, it is worth noting that these pro-
ducts have not been rigorously tested for their claims.
s00303.2 (2)-Epigallocatechin-3-Gallate
p0120(2)-Epigallocatechin-3-gallate is a green-tea derived
catechin polyphenol (i.e., flavanol). Several studies
reported on the potential benefits of topical applica-
tions of EGCG for preventing or treating skin condi-
tions. Indeed, EGCG displays a number of features
such as anti-inflammatory, antioxidant and DNA
repair activities.
11
p0125A recent ex-vivo study showed that EGCG was able
to reduce the cell death caused by exposure of human
HaCaT cells to SNP, although this effect was much
lower than that observed with resveratrol.
55
Also,
EGCG treatment of human fibroblasts in culture
blocked UV-induced collagen secretion and collage-
nase transcriptional levels, and inhibited the binding
activities of the UV-induced nuclear transcription fac-
tors NF-κB and activated protein (AP-1).
62
Treatment
of normal human epidermal keratinocytes with EGCG
could inhibit UVB-induced intracellular release of
H
2
O
2
concomitantly with the inhibition of UVB-
induced oxidative stress-mediated phosphorylation of
epidermal growth factor receptor (EGF-R) and MAPKs
signaling pathways.
63
p0130Besides, topical treatment of SKH-1 hairless
mouseskinwithEGCGinahydrophilicointment
significantly inhibited UVB-induced skin tumor
development.
64
In another study,
65
topical treatment
ofhumanskinwithEGCGpriortoUVBexposure
significantly reduced the: (1) UVB-induced infiltra-
tion of inflammatory leukocytes, (2) UVB-induced
NO and H
2
O
2
production, which was in accordance
822 63. POLYPHENOLS AGAINST SKIN AGING
6. DIVERSE DISEASE AND PHYSIOLOGICAL STATES MODIFIED BY POLYPHENOLS
Watson 978-0-12-398456-2 00063
To protect the rights of the author(s) and publisher we inform you that this PDF is an uncorrected proof for internal business use only by the author(s), editor(s), reviewer(s), Elsevier
and typesetter MPS. It is not allowed to publish this proof online or in print. This proof copy is the copyright property of the publisher and is confidential until formal publication.
with the effect of (1) above, (3) UVB-induced produc-
tion of prostaglandin (PG) metabolites, including
PGE
2
,PGF
2α
,andPGD
2
, which play a critical role in
inflammatory disorders and in proliferative skin dis-
eases. In separate experiments, it has been shown
that topical treatment with EGCG in the skin of mice
significantly inhibits acute or chronic UV irradiation-
induced protein oxidation.
66
Independent studies
observed an exceptionally high photo-protective
effect of EGCG against UV radiation-induced oxida-
tive stress (e.g., lipid peroxidation, H
2
O
2
production)
and depletion of antioxidant defense enzymes (e.g.,
catalase, GSH, and SOD levels).
64,67
Further, a study
in mouse skin evaluating DNA repair mechanisms
suggestedthattherapidrepairofUV-inducedcyclo-
butane pyrimidine dimers (CPDs) by topically
applied EGCG is mediated through stimulation of
the cytokine interleukin-12 (IL-12).
68
Taken together,
these studies suggested that EGCG might prevent
skin aging and related diseases (e.g., photo-induced
skin cancers) in humans.
p0135 Topical application of EGCG to the skin is preferred
to oral administration, owing to the consideration that
this large molecular weight polyphenol is poorly
absorbed through the gut barrier (i.e., in the gut
mucosa and inner tissues).
69
Topical cream-based for-
mulations of EGCG for human use have been devel-
oped, and their photo-protective effects have been
evaluated using animal models.
s0035 3.3 Genistein
p0140 The soybean isoflavone genistein (aglycone) is a
potent antioxidant, a specific inhibitor of protein tyro-
sine kinase, and a phytoestrogen.
70
In the past decade,
a series of studies and reports demonstrated that
genistein (as topical, oral or systemic agent) has signifi-
cant anti-photocarcinogenic and anti-hotoaging effects,
suggesting considerable promise as an effective agent
against the aging process in humans.
7075
Indeed, a
study showed that genistein was able to greatly
decrease the H
2
O
2
increment in human keratinocytes
caused by UVB radiation.
70,71
Also, in a recent study
using dermal fibroblasts, it was demonstrated that
genistein protects UVB-induced senescence-like char-
acteristics (e.g., senescence-associated beta-galactosi-
dase (SA-β-gal), apoptosis) via maintenance of
antioxidant enzyme activities and modulation of mito-
chondrial oxidative stress (i.e., inhibition of the fork-
head protein FKHRL1 expression, induction of SOD
and malondialdehyde (MDA) levels) through down-
regulation of the 66-kilodalton isoform of the growth
factor adapter Shc (p66Shc)-dependent signaling
pathway.
72
p0145An in vivo study showed that pretreatment of
human skin with genistein inhibited UV-induced EGF-
R tyrosine kinase activity as well as both extracellular
signal-regulated kinase (ERK) and c-Jun N-terminal
protein kinase (JNK) activities.
73
In this same study,
genistein did not protect against UV-induced ery-
thema, suggesting that it is unlikely to act as a sun-
screen.
73
Interestingly, a recent double-blind,
randomized, placebo-controlled trial, indicated that
oral intake of 40 mg genistein per day safely improves
the aged skin of middle-aged women (n526).
74
Further, a most recent study conducted in aged rats
demonstrated the potential benefit of relatively long-
term systemic treatment with genistein to “revert”
some molecular, histological and functional changes of
the skin associated with ovariectomy (e.g., decrease in
transforming growth factor-beta 1 (TGF-β1), vascular
endothelial growth factor (VEGF), MMP-2, MMP-9, tis-
sue inhibitor of MMP (TIMP)-1 and TIMP-2).
75
This
in vivo study meantime suggested that genistein might
be an effective alternative therapy for the management
of age-related skin changes in postmenopausal
women.
75
s00404. OTHER POLYPHENOLS WITH
POTENTIAL ANTI-AGING CAPACITY:
EMERGING STUDIES
s00454.1 Tannic and Ellagic Acids
p0150Ellagic acid (EA) and tannic acid (TA) are phenolic
acids found in a wide variety of fruits and nuts such
as raspberries, strawberries, pomegranate, walnuts,
grapes, and blackcurrants.
76,77
These molecules are
receiving attention as agents that may have potential
bioactivities preventing chronic diseases and skin
aging. Indeed, they possess potent ability to scavenge
ROS and reactive nitrogen species (RNS).
77
Further,
EA was shown to decrease the expression of pro-
MMP-2 and pro-MMP-9, precursors of two elastolytic
enzymes.
78
Besides, TA was shown to bind to insolu-
ble bovine and porcine elastin, and inhibit their degra-
dation by porcine pancreatic elastase.
79
More recently,
data have indicated that treatment of cultured human
dermal fibroblasts and organ cultures of human skin
biopsies with lipophilic EA and/or hydrophilic TA sig-
nificantly (and synergistically) enhances their net
deposition of elastic fibers (i.e., elastogenesis), by a
mechanism that, once the elastogenic compounds are
bound to purified elastin, premature proteolytic degra-
dation of both tropoelastin and fully polymerized elas-
tin (major component of mature elastic fibers) are
prevented from elastolytic enzymes (e.g., serine protei-
nases, cysteine proteinases, and MMPs).
9
This finding
8234. OTHER POLYPHENOLS WITH POTENTIAL ANTI-AGING CAPACITY: EMERGING STUDIES
6. DIVERSE DISEASE AND PHYSIOLOGICAL STATES MODIFIED BY POLYPHENOLS
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has particular implications for the treatment of pediat-
ric patients with inherited skin aging (i.e., Werner’s
syndrome, Costello’s syndrome or Cutis Laxa), who
generally present impaired primary deposition of elas-
tic fibers and subsequent wrinkles and deep dermal
creases.
9
Concordingly, a recent study examining the
photoprotective effects of EA on collagen breakdown
and inflammatory responses in UVB-irradiated human
skin cells (HaCaT keratinocytes, human dermal fibro-
blasts) and hairless mice (SKH-1), showed that EA pre-
vents collagen destruction and inflammatory responses
caused by UVB.
80
Indeed, in this study, EA: (1)
markedly prevented collagen degradation by blocking
matrix MMP production in UVB-exposed fibroblasts,
(2) attenuated UVB-triggered skin wrinkle formation
and epidermal thickening in hairless mice, (3) dimin-
ished the production of pro-inflammatory cytokines
IL-1βand IL-6 and blocked infiltration of inflammatory
macrophages in the integuments, when topically
applied to hairless mice chronically exposed to UVB,
and (4) mitigated inflammatory intracellular cell adhe-
sion molecule-1 (ICAM-1) expression in UVB-irradi-
ated keratinocytes and hotoaged mouse epidermis.
p0155 Eventually, these studies showed that topical appli-
cation of TA and/or EA may represent promising
treatment strategies interrupting skin wrinkle and
inflammation associated with skin aging.
s0050 4.2 Quercetin, Dihydroquercetin and
Quercitrin
p0160 Quercetin, dihydroquercetin and quercitrin are fla-
vonoids (flavonols) found in various vegetarian foods
including onions.
13,14
Research studies suggest that
quercetin may act to prevent the development of can-
cers
81,82
and skin aging.
83
Interestingly, a study
showed that quercetin, alone or in cooperation with
ascorbic acid (vitamin C), is able to protect neurovas-
culature structures in skin from injury induced by oxi-
dative stress, and thus may be of therapeutic benefit
against skin aging.
83
Indeed, quercetin (EC
50
:
3040 μM) protected cutaneous tissue-associated cell
types (i.e., human skin fibroblasts, keratinocytes, and
endothelial cells) from injury (i.e., cell death) induced
by intracellular peroxides generated by buthionine sul-
foximine (BSO), an irreversible inhibitor of glutathione
(GSH) synthesis.
83
p0165 Dihydroquercetin (taxifolin) is a potent flavonoid
that can also be found in the market in its semi-
synthetic form under the trade name of Venoruton
s
.
84
The therapeutic promise of dihydroquercetin in major
inflammatory disease states such as cancer was
recently reviewed.
84
In particular, it was reported that
dihydroquercetin can act as a scavenger of
myeloperoxidase (MPO)-derived RNS.
84
Interestingly,
and although the efficacy was lower than that
observed with quercetin, dihydroquercetin was able to
decrease BSO-induced injury to dermal fibroblasts.
83
Further, a most recent controlled study, showed that
dihydroquercetin was able to downregulate the colla-
genase I (MMP-1) in UVB-treated skin cells.
85
p0170Although there is still a paucity of reports associat-
ing quercitrin with skin aging, a promising recent
study revealed a cytoprotective effect of this com-
pound on UVB-induced cell injury in human keratino-
cytes (HaCaT).
86
As a result, it was showed that the
intracellular ROS and cell death generated by the
exposure of HaCaT cells to UVB radiation were signifi-
cantly decreased after treatment with quercitrin.
86
p0175Overall data therefore suggest that the three flavo-
nols: quercetin, dihydroquercetin and quercitrin, may
present benefits to delay skin aging in humans.
s00554.3 Equol
p0180S-Equol, a non-steroidal estrogen (17βestradiol), is a
soy-derived isoflavonoid molecule produced by the
metabolism of the isoflavone daidzein by intestinal
flora.
87
To date, the evidenced primary mechanism of
action of this antioxidant is to activate estrogen recep-
tor-β(ER-β), which in turn enhances the expression of
antioxidant enzymes and inhibits the expression of
snail, a transcription factor that regulates keratinocyte
cell proliferation and migration.
88
A recent study
showed that equol can influence expression of skin
genes and proteins (i.e., increased collagen I and III,
elastin, and TIMPs levels; decreased MMPs gene
expression) using human monolayer fibroblast and
three-dimensional organotypic cultures.
89
p0185Altogether, the current findings suggest that equol:
(1) is a scavenger of free radicals to prevent skin dam-
age and skin aging, (2) has the potential to be used
topically for the treatment and prevention of skin
aging, by enhancing ECM components in human skin,
and (3) could be a safer ER-βagent than typical estro-
gen chemotherapy.
s00605. POLYPHENOLS EXTRACTS: MAY THE
RINGS MAKE THE DIFFERENCE TO
FIGHT AGING?
p0190Relevant studies associating polyphenol-rich plant
extracts (i.e., neutraceutics or cosmeceutics) such as
herbs (e.g., tea), fruits (e.g., grapes, pomegranate),
vegetables (e.g., soy), cereals (e.g., sorghum) or nuts
(e.g., almonds) with skin aging are reviewed. Currently,
only products such as green and black tea, soy,
824 63. POLYPHENOLS AGAINST SKIN AGING
6. DIVERSE DISEASE AND PHYSIOLOGICAL STATES MODIFIED BY POLYPHENOLS
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pomegranates, and dates have had clinical trials pub-
lished for the treatment of extrinsic aging.
90
Increasing
evidence has shown that regular and
acceptable consumption or application of these products
can delay the process of skin aging and related skin
diseases.
s0065 5.1 Tea
p0195 Herbs have been used in medicines and cosmetics
for centuries. Indeed, herbal preparations, such as
green tea extracts, have gained popularity as ingredi-
ents in topical skin care (i.e., in the improvement of
skin appearance, treatment of different skin diseases,
skin rejuvenation, and prevention of photo-damage).
91
Although isolated plant compounds have shown a
high potential for protecting the skin, whole herb
extracts, such as green tea (Camellia sinensis), generally
showed better potential due to their complex
composition.
92
p0200 Green tea polyphenolic (GTP) compounds (e.g.,
EGCG, cf. Section 3.2) display significant antioxidant
and anti-inflammatory activities. Studies in humans
and animal models suggest that GTP extracts can pre-
vent cutaneous adverse effects of UVR (e.g., premature
skin aging, skin cancers, erythema) or improve hoto-
aging skin.
68,9395
p0205 Thereby, a study led in SKH-1 hairless mice and in
human skin fibroblast HS68 cells, strongly suggested
that oral GTP (i.e., as dietary supplement) could be
useful to attenuate solar UVB light-induced premature
skin aging (i.e., oxidative damage such as protein oxi-
dation and induction of MMPs such as MMP-2, -3, -7
and -9).
68
Interestingly, a randomized study involving
women with moderate hotoaging (n540) has evalu-
ated the effects of a combination regimen of topical
(i.e., green tea cream) and oral green tea supplementa-
tion on the clinical and histologic characteristics of
hotoaging. While no significant differences in clinical
grading were found between the green tea-treated and
placebo groups, histologic grading of skin biopsies did
show significant improvement in the elastic tissue con-
tent of treated specimens.
93
Further, a recent double-
blind, placebo-controlled trial of adult women (n556)
that aimed to evaluate the long-term effects of oral
GTPs on the clinical and histologic characteristics of
hotoaging skin, revealed that GTPs contribute to sig-
nificant improvement in overall solar damage, at least
during the 24 months of use.
94
Most recently, an inde-
pendent in vivo study reported that green tea and black
tea extracts incorporated in dermal gels were able to
confer protection against the harmful effects of UVR.
95
This effect of strong UV absorbance elicited by these
herbs was explained by the possible cooperative action
of their overall alkaloids; in particular, their polyphe-
nolic fraction.
95
Indeed, when aqueous extracts (i.e.,
gels) of black and green tea were tested in vivo in the
forearms of a few subjects (n56) using an artificial UV
(200400 nm) source, peaks were found for catechins
(e.g., EGCG) and polyphenols with dimeric and poly-
meric structures (e.g., theaflavins and thearubigins).
95
s00705.2 Coffee
p0210Coffee berry (Coffea arabica L.) is a natural ingredient
that has promising efficacy in the topical treatment of
oxidative stress-induced pathologies (e.g., premature
skin aging, dermatoses), and its seed oil is widely used
in cosmetic formulations.
42,9698
Indeed, it was recently
shown that Coffea arabica leaf extract, naturally rich in
polyphenols, can prevent photo-damage in skin
through: (1) stimulation of type I pro-collagen, (2) inhi-
bition of MMP expression (i.e., MMP-1, -3, -9), and (3)
inhibition of MAPK pathway (i.e., phosphorylation of
JNK, ERK and p38 MAPK).
42
Further, an in vitro study
showed protective effects of green Coffea arabica oil
(GCO) in human skin cells and explants.
97
Indeed, in
human skin fibroblasts, GCO produced a dose-
dependent stimulation in the synthesis of collagen,
elastin, and GAGs, in addition to increasing the release
of TGF-β1 and granulocyte-macrophage colony-
stimulating factor (GM-CSF).
97
Also, in cultured kerati-
nocytes and human skin explants, GCO induced a
significant transcriptional expression of the water-
channel aquaglycerolporins-3 (AQP-3).
97
Interestingly,
in a recent double-blinded, randomized, controlled
clinical usage study led with Caucasian female partici-
pants (n540), a novel topical, highly antioxidant poly-
phenolic skin care system containing Coffea arabica
produced statistically significant improvements in the
appearance of photo-damaged/hotoaged skin (e.g.,
reduced wrinkles, hypo-pigmentation, decreased blot-
chy redness and tactile roughness), and demonstrated
that the antioxidant skin care system was well toler-
ated, with no adverse events reported by the partici-
pants during the course of the study.
98
s00755.3 Grapes
p0215Grape seeds are waste products of the wine and
grape juice industry. However, these seeds contain
lipids, proteins, carbohydrates, and 58% polyphenols
(mainly flavonoids such as proanthocyanidins)
depending on the variety of grape.
99
Grape seed
extract exerts a powerful antioxidant effect to bond
with collagen, and has been shown to notably protect
the body from premature (skin) aging.
99
Also, grape
wine extracts exert protective effects against aging in
8255. POLYPHENOLS EXTRACTS: MAY THE RINGS MAKE THE DIFFERENCE TO FIGHT AGING?
6. DIVERSE DISEASE AND PHYSIOLOGICAL STATES MODIFIED BY POLYPHENOLS
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and typesetter MPS. It is not allowed to publish this proof online or in print. This proof copy is the copyright property of the publisher and is confidential until formal publication.
general, notably because of the presence of the antioxi-
dant polyphenol resveratrol.
13—14,99
Thereby, in an
in vitro study using a three-dimensional tissue culture
model of human epidermis, a grape wine extract was
able to prevent skin oxidative damage induced by
UVB exposure (e.g., reduction of GSH and inflamma-
tory molecules such as IL-1 and PGE).
100
s0080 5.4 Pomegranate
p0220 Pomegranate (Punica granatum L.) is a kind of fruit
consumed fresh or in beverage, and has been widely
used in traditional medicine in various parts of the
world because of its strong antioxidant and anti-
inflammatory properties.
101
The polyphenol content of
this fruit (i.e., catechin, quercetin, kaempferol, and
equol) is known to prevent adverse cutaneous effects of
UV irradiation.
101,102
Indeed, an extract of the Korean
red P. granatum was able to protect cultured human
skin fibroblasts against UVB-induced damage.
101
Thereby, the P. granatum extract, especially the one pre-
pared from rind, collagen synthesis was increased and
MMP-1 expression was decreased.
101
Concordantly,
another study showed that pretreatment of human
immortalized HaCaT keratinocytes with a polyphenol-
rich pomegranate fruit extract inhibited UVB-induced
oxidative stress and hotoaging,
102
in the following
ways: (1) upregulation of MMP-1, -2, -7 and -9 protein
levels, (2) decrease in TIMP-1 protein level, (3) phos-
phorylation of MAPKs, and (4) phosphorylation of
c-Jun but not c-fos. These results suggest that POMx
protects HaCaT cells against UVB-induced oxidative
stress and markers of hotoaging and could be a useful
supplement in skin care products.
102
p0225 Essentially, these few studies suggest that dietary
consumption of this fruit and its use as a supplement in
skin care products can be valuable against skin aging.
s0085 5.5 Soybean
p0230 Soybeans are known to contain isoflavones (e.g.,
genistein and daidzein) with beneficial biological
activity in the skin (e.g., reduction of ROS and skin
hyper-pigmentation; stimulation of collagen synthesis,
cellular GSH content and glutathione S-transferase
(GST) activity; prevention of ODC; increased moisture
and GAGs such as hyaluronic acid (HA)).
71,103,104
It is
still unclear whether soy isoflavones act as antioxi-
dants themselves or affect cell signaling processes that
increase the skin’s own antioxidant capabilities.
71
Nonetheless, studies showed that the soybean isofla-
vones, genistein and daidzein, were able to greatly
decrease the H
2
O
2
increment in human keratinocytes
caused by UVB radiation,
71,72
suggesting that topical
soybean extracts may be capable of preventing the bio-
chemical alteration associated with aging.
105
Interestingly, and albeit weaker activity than estradiol,
genistein and daidzein are considered as potent phyto-
estrogens which can bind to α- and β-estrogen recep-
tors of the skin to retard skin thinning and collagen
loss associated with postmenopause.
24,106108
Interestingly, a double blind, vehicle-controlled clinical
study involving women (n565) with moderate facial
photo-damage, demonstrated the efficacy and safety of
a novel soy moisturizer in skin aging (i.e., improve-
ments in mottled pigmentation, blotchiness, dullness,
fine lines, overall texture, overall skin tone, and overall
appearance).
106
Recently, an in vitro and in vivo study,
that aimed to evaluate the effects and possible
mechanisms of an isoflavone extract from soybean
cake against UVB-induced skin damage,
109
revealed
the following: (1) reduced cell death and decreased
phosphorylation of p38 MAPK, JNK, and ERK1/2 in
UVB-treated HaCaT cells, (2) and decreased epidermal
thickness and the expressions of COX-2 and PCNA as
well as increased of catalase in ICR-Foxn/(nu) mice
treated with topical application of isoflavone extract
before UVB.
p0235Overall, these data show that soy extracts can con-
tribute to the prevention of skin aging, notably
through inhibition of ROS, UVB-induced apoptosis
and inflammation.
s00906. OTHER POLYPHENOL EXTRACTS
WITH POTENTIAL ANTI-AGING
CAPACITY: EMERGING STUDIES
s00956.1 Cacao
p0240Cacao (aka cocoa) bean is a popular edible plant that
contains polyphenols and xanthine derivatives.
Interestingly, an in vivo study showed that topical appli-
cation of cacao bean extracts to the dorsal skin of hairless
mice exposed to solar UV-like radiation suppressed
photo-damage such wrinkle formation, dermal connec-
tive alteration, and collagen accumulation.
110
Cacao bean
extract also possesses protective effects against UV-
induced erythema when taken orally, and an H
2
O
2
-scav-
enging effect.
110
s01006.2 Apples
p0245Apples (sp. Malus domestica) contain nutrients and
other compounds of interest, including high levels of
polyphenols (e.g., triterpenoids in peel, anthocyanins
in red apples).
111114
Oligomeric proanthocyanidins
give the largest contribution to the antioxidant activity
of apple extracts.
112
While numerous studies
826 63. POLYPHENOLS AGAINST SKIN AGING
6. DIVERSE DISEASE AND PHYSIOLOGICAL STATES MODIFIED BY POLYPHENOLS
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and typesetter MPS. It is not allowed to publish this proof online or in print. This proof copy is the copyright property of the publisher and is confidential until formal publication.
undertaken in recent years have shown that apples
and their derivatives may have a wide range of biolog-
ical activities and benefits in several diseases (e.g., can-
cers, cardiovascular diseases), studies evaluating
beneficial effects of apple extracts on aging in mamma-
lian skin are lacking. Instead, yeast has appeared as a
valuable model organism to study aging.
115
Thereby, a
recent and interesting study in yeast strains (e.g.,
Saccharomyces cerevisiae) showed that apple extracts are
able to increase lifespan of mutants (e.g., Kllsm4Δ) that
shows premature aging and cell death.
116
The best
result was obtained with the whole fruit, indicating a
cooperative role of all apple components
116
s0105 6.3 Sorghum brans
p0250 Sorghum varieties deserve consideration as possible
nutraceutical and cosmeceutical ingredients for func-
tional skin care, foods, and beverages. Indeed, while
black sorghum cultivar lacks condensed tannins
(proanthocyanidins), it has abundant anthocyanins
and other polyphenols.
43
A relatively recent study
revealed the ability of ethanolic extracts of bran from
six cultivated varieties of sorghum bicolor to inhibit
hyaluronidase activity in vitro, when compared to
extracts of wheat and rice bran.
43
Thereby, black sor-
ghum exhibited more potency to inhibit hyaluronidase
than white sorghum, and sorghum varieties displayed
more potency than wheat and rice bran.
Hyaluronidase inhibition correlated positively with
total phenolic content and ferric reducing antioxidant
power values for each bran extract.
p0255 This finding is quite interesting because the balance
between HA and hyaluronidase activity (i.e., GAGs
hydrolysis) in ECM influences tissue repair, tissue remo-
deling and maintenance of skin hydration,
43,117
and so
plays a role in preserving the skin against aging.
s0110 7. CONCLUSIONS
p0260 The traditional use of plants in medication (e.g.,
skin anti-aging and associated diseases) or beautifica-
tion (e.g., cosmetics) is the basis for active but chal-
lenging research, and should make new trends in
cosmetics and medical therapy. Polyphenols are
believed to have photo-protective anti-aging effects
through decreasing inflammation and acting as a scav-
enger of free radicals. For many compounds, a large
number of well-conducted clinical studies are required
to prove their safety and efficacy before they are used
as anti-aging cosmeceutics, anti-aging neutraceutics, or
as adjuvant therapeutics. Besides, the complexity of
polyphenol-rich extracts of the whole food product
(e.g., mix of vitamins such as C and E, pigments such
as carotenoids) or polyphenol-rich blends (e.g., sea
buckthorn (Hippophae rhamnoides L.) fruit blend) might
be more beneficial to treat skin conditions (e.g., skin
aging) than the pure, selected polyphenols. However,
highly purified polyphenols are important for the
study of biological effects and in unraveling mechan-
isms of action. Essentially, clinical studies combining
pure polyphenols, polyphenol extracts or polyphenol-
based nano-formulations with other modalities (e.g.,
chemotherapeutics, sunscreens, techniques used in
esthetics) in order to increase their respective efficacy,
are lacking.
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830 63. POLYPHENOLS AGAINST SKIN AGING
6. DIVERSE DISEASE AND PHYSIOLOGICAL STATES MODIFIED BY POLYPHENOLS
Watson 978-0-12-398456-2 00063
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NON-PRINT ITEM
Abstract
The skin is the largest organ of the body with a surface area of approximately 1.52.0 m
2
. It protects the inter-
nal organs of the body by acting as an effective barrier against the detrimental effects of environmental and xeno-
biotic agents (e.g., extrinsic harmful chemicals and genotoxics). Strong or chronic exposition to a variety of
external stresses (e.g., ultraviolet radiation aka solar UV) may contribute to premature skin aging, immune-
suppression, and tumorigenesis/carcinogenesis (i.e. tumor/cancer formation). Therefore, a search for prevention
strategies to circumvent such unfavorable outcomes is being constantly pursued. Polyphenols (aka polyhydroxy-
phenols) represent a superfamily of diverse naturally occurring phytochemicals. An increasing number of studies
on vertebrates and invertebrates have shown that these compounds modulate many signaling pathways, and
subsequently exert numerous biological activities (e.g., significant antioxidant, chemopreventive, immune-modu-
latory, cell repair and photo-protective effects) as well as potential health benefits (e.g., prevention of aging,
reduction in cancer incidences and other inflammatory-state diseases). Among the several hundreds of dietary
polyphenols (plant nutraceuticals aka phytonutrients), some constitute a promising approach to remedying many
skin conditions (i.e., prevention and treatment of skin aging and diseases). The protective skin aging effects
exhibited by polyphenols may, however, partially depend on their molecule characteristics, the food matrix,
and/or on their bioavailability, which does not always depend on the overall intake/consumption. Eventually,
natural purified polyphenols or polyphenol-rich plant extracts (semi-synthetic or synthetic) might supplement
skin chemotherapeutics, our sun protection armamentarium, and further enhance the benefit of esthetic techni-
ques (e.g., microdermabrasion). Thereby, polyphenols are also gaining popularity as ingredients in cosmetic for-
mulations (cosmeceuticals). In this chapter, we outline the current progress in skin aging intervention studies
using polyphenols (e.g., purified polyphenols, dietary, or topical rich-polyphenols products).
Keywords: Anti-aging; antioxidants; cosmeceuticals; nutraceuticals; polyphenols; skin rejuvenation.
Watson 978-0-12-398456-2 00063
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and typesetter MPS. It is not allowed to publish this proof online or in print. This proof copy is the copyright property of the publisher and is confidential until formal publication.
... Improving the skin and gill immune status will result in better defense of fish species during constant exposure to contaminated aquatic environments induced by chemical substances and/or pathogenic agents. Even though the mechanism by which GSE could improve the immune defense of fish skin is unclear, in previous studies, the possible mechanism of action was always related to the proanthocyanidins from grape seeds (Nichols and Katiyar 2010;Menaa et al. 2014). It was proved that these bioactive compounds induce different signaling pathways which lead to many biological effects including anti-inflammation, immunomodulation, repair in damaged-tissues, and photo-protection, which have been demonstrated on skin disorders both in humans and laboratory animals (Nichols and Katiyar 2010;Menaa et al. 2014). ...
... Even though the mechanism by which GSE could improve the immune defense of fish skin is unclear, in previous studies, the possible mechanism of action was always related to the proanthocyanidins from grape seeds (Nichols and Katiyar 2010;Menaa et al. 2014). It was proved that these bioactive compounds induce different signaling pathways which lead to many biological effects including anti-inflammation, immunomodulation, repair in damaged-tissues, and photo-protection, which have been demonstrated on skin disorders both in humans and laboratory animals (Nichols and Katiyar 2010;Menaa et al. 2014). ...
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... Ellagic acid, a polyphenol mainly found in fruits and vegetables, well studied for its antioxidant, antimutagenic, and anticancer properties [52,53], was determined in white quinoa seeds (Table 4), while no studies are currently available on the presence of this phenolic acid in pigmented varieties. Gallic acid, for which antihyperglycemic, anti-lipid peroxidative, and antioxidant effects have been claimed [54], was mainly investigated in white quinoa seeds, but there is also evidence of gallic acid in a sample of black quinoa [20] ( Table 4). ...
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... Since many polyphenols derived from natural sources have low solubility, low bioavailability, and poor stability [105,106], there has been a growing trend to utilize nano-formulations and emulsions to bypass the limiting pharmacokinetics of each polyphenol and increase efficacy [107][108][109]. Although TRSV has 80% bioavailability when taken orally, these technologies could still help decrease metabolism and increase the half-life of TRSV, which is only 104 min [110]. ...
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Identifying effective anti-aging compounds is a cornerstone of modern longevity, aging, and skin-health research. There is considerable evidence of the effectiveness of nutrient signaling regulators such as metformin, resveratrol, and rapamycin in longevity and anti-aging studies; however, their potential protective role in skin aging is controversial. In light of the increasing appearance of phytocannabinoids in beauty products without rigorous research on their rejuvenation efficacy, we decided to investigate the potential role of phytocannabinoids in combination with nutrient signaling regulators in skin rejuvenation. Utilizing CCD-1064Sk skin fibroblasts, the effect of metformin, triacetylresveratrol, and rapamycin combined with phytocannabinoids on cellular viability, functional activity, metabolic function, and nuclear architecture was tested. We found triacetylresveratrol combined with cannabidiol increased the viability of skin fibroblasts (p < 0.0001), restored wound-healing functional activity (p < 0.001), reduced metabolic dysfunction, and ameliorated nuclear eccentricity and circularity in senescent fibroblasts (p < 0.01). Conversely, metformin with or without phytocannabinoids did not show any beneficial effects on functional activity, while rapamycin inhibited cell viability (p < 0.01) and the speed of wound healing (p < 0.001). Therefore, triacetylresveratrol and cannabidiol can be a valuable source of biologically active substances used in aging and more studies using animals to confirm the efficacy of cannabidiol combined with triacetylresveratrol should be performed.
... Hence, this substructure in Taxifolin and Rutin could be responsible for their antiviral activity. Taxifolin has been reported to exhibit several pharmacological activities and has been reported to act as an antioxidant, control inflammation, manage oxidative stress, and showed a protective effect in several cardiovascular diseases, liver disorders, bone disorders, skin disorders, etc. [55][56][57][58]. Further, this molecule has good water solubility comparative to other flavonoids, due to which it shows good bioavailability in the organs to show its effect [59]. ...
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... A substantial literature supports the biological plausibility of multiple dietary and lifestyle exposures contributing to oxidative stress. Increasing evidence supports that higher intakes of certain nutrients, including carotenoids (e.g., lycopene, β-carotene, and lutein) [31,32], vitamin C [33], vitamin E [34], selenium [35], omega-3 fatty acids [36,37], and flavonoids [38][39][40][41], and regular physical activity [42], may protect against oxidative stress. ...
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